Dual IRE1 RNase functions dictate glioblastoma development

Stéphanie Lhomond,Dimitrios Doultsinos,Nicolas Dejeans,Gwénaële Jégou,Amandine Etcheverry,Olga Papadodima,Kathleen Schmit,Jean Mosser,Konstantinos Voutetakis,Aristotelis Chatziioannou,Claudio Hetz,Tony Avril,Mari Mcmahon,Kim Barroso,Marianthi Logotheti,Afshin Samali,Joanna Obacz,Florence Jouan,Raphaël Pineau,Olivier Pluquet,Véronique Quillien,Héloïse Bourien ,Élodie Vauléon ,Pierre-Jean Le Reste ,John B Patterson ,Néstor Pallares-Lupon ,M Maurel ,Éric Chevet

doi:10.15252/emmm.201707929

Abstract

Proteostasis imbalance is emerging as a major hallmark of cancer, driving tumor aggressiveness. Evidence suggests that the endoplasmic reticulum (ER), a major site for protein folding and quality control, plays a critical role in cancer development. This concept is valid in glioblastoma multiform (GBM), the most lethal primary brain cancer with no effective treatment. We previously demonstrated that the ER stress sensor IRE1α (referred to as IRE1) contributes to GBM progression, through XBP1 mRNA splicing and regulated IRE1‐dependent decay (RIDD) of RNA. Here, we first demonstrated IRE1 signaling significance to human GBM and defined specific IRE1‐dependent gene expression signatures that were confronted to human GBM transcriptomes. This approach allowed us to demonstrate the antagonistic roles of XBP1 mRNA splicing and RIDD on tumor outcomes, mainly through selective remodeling of the tumor stroma. This study provides the first demonstration of a dual role of IRE1 downstream signaling in cancer and opens a new therapeutic window to abrogate tumor progression.

Highlights

Glioblastoma multiforme (GBM) is one of the most lethal adult cancers, as the majority of patients die within 15 months after diagnosis (Anton et al, 2007)
We showed the relevance of IRE1 signaling in GBM from two independent cohorts (TCGA and GBMmark) and found that high IRE1 activity correlates with shorter patient survival and increased tumor infiltration by immune cells, increased tumor angiogenesis, and enhanced invasion/migration properties of the tumor cells (Fig 1)
Previous studies demonstrated the importance of IRE1 signaling for tumor aggressiveness; they did not provide any information on the underlying molecular mechanisms involved in this phenomenon

Summary

Introduction

Glioblastoma multiforme (GBM) is one of the most lethal adult cancers, as the majority of patients die within 15 months after diagnosis (Anton et al, 2007). To limit tumor recurrences from invasive cells, chemotherapy [temozolomide (TMZ)] was added to surgery and radiation (Stupp et al, 2005). This combined therapy has demonstrated some efficiency, it only increases patient’s median a 2018 The Authors. IRE1 signaling in GBM Stéphanie Lhomond et al survival from 12.1 to 14.6 months. Understanding biological processes of GBM progression and treatment resistance represents a major challenge to develop more effective therapies

Methods

Results

Conclusion